4-Phenyl-and 5-phenyl-1,4,5,6-tetrahydropyrimidine derivatives

ABSTRACT

Certain 1,4,5,6-tetrahydropyrimidine compounds which are substituted with an amino, amido or carbamate at the 2-position, with an optionally substituted phenyl at the 5-position or at the 4-position when there is no alkyl at the 1-position and optionally a lower alkyl at the 1-position when the phenyl is at the 5-position are useful as CNS agents and as antihypertensives.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 1,4,5,6-tetrahydropyrimidines which aresubstituted at the 4 or 5 position with a phenyl or substituted phenyland at the 2 position with an amino, alkylcarbonylamino oralkoxycarbonylamino and the pharmaceutically acceptable salts thereof.The compounds can be combined with suitable pharmaceutical excipients toprepare pharmaceutical compositions which are useful for treatingdisorders of the central nervous system or cardiovascular system. Theinvention further relates to methods of preparing the compounds of theinvention.

2. Prior Art

A general discussion of psychotic disorders and the use of psychotropticdrugs can be found in the Pharmacological Basis of Therapeutics, 4thEdition, L. S. Goodman and A. Gilman, Editors, McMillan Company, NewYork (1970).

It is known that certain 2-amino-4-aryl-2-imidazolines showantihypertensive activity. (See Journal of Medicinal Chemistry, Vol. 16,No. 8, p. 901 (1973)). It is also known that certain4,5-dihydro-5-phenyl-2-lower alkoxycarbonylaminoimidazoles, thesubstituted phenyl derivatives thereof, and the n-alkyl derivatives areuseful for treating disorders of the central nervous system. See forexample U.S. Pat. No. 4,088,771 to Roszkowski et al and U.S. Pat. No.4,129,661 to Roszkowski, et al.

U.S. Pat. Nos. 3,895,112 and 3,707,560 both to DeAngelis and Hessdisclose 4-amino-6-aryl-pyrimidines which are useful as musclerelaxants, bronchodilators, and/or platelet aggregation inhibitors.Also, U.S. Pat. No. 2,735,225 to Goodhue and Mahan of Phillips Petroleumdescribes certain pyrimidines, for example,4-phthalimido-2,6-dimethylpyrimidine, which are useful as plant growthregulators. It is also known that certain tetrahydropyrimidines, such as1-methyl-2-(2-thienylethenyl)-tetrahydropyrimidine, are useful asanthelmintic agents used in veterinary practice. See, for example,Organic Chemistry of Drug Synthesis, Lednicer and Uitscher, pp. 266-267,John Wiley and Sons (1977).

An entirely new group of tetraphydropyrimidines has now been discoveredwhich is useful in the treatment of disorders of the central nervoussystem and/or the cardiovascular system.

SUMMARY OF THE INVENTION

The compounds of the invention are represented by the formula ##STR1##wherein

A is hydrogen, RC(O)-- or ROC(O)--;

R is alkyl of one through six carbon atoms;

R¹ is hydrogen or alkyl of one through six carbon atoms;

X is hydrogen, fluoro, chloro, bromo, iodo, alkoxy of one through fourcarbon atoms, benzyloxy, hydroxy, alkyl of one through four carbonatoms, alkylthio of one through four carbon atoms, alkyl sulfinyl of onethrough four carbon atoms, alkyl sulfonyl of one through four carbonatoms, trifluoromethyl or hydrogen;

Y is hydrogen or is the same as X, and

the phenyl substituent carrying the X and Y is at the 4 or 5 position ofthe tetrahydropyrimidine ring when R¹ is hydrogen or is at the5-position when R¹ is alkyl.

Pharmaceutically acceptable salts of the above compounds are alsoencompassed within the scope of the invention.

Another aspect of the invention is a pharmaceutical composition whichcomprises a compound chosen from those represented by Formula I or apharmaceutically acceptable salt thereof along with a suitablepharmaceutical excepient.

Still another aspect of the invention is the administration of acompound of the invention to an animal to treat disorders of the centralnervous system, for example, depression, anxiety, convulsions, centrallyinduced skeletal muscle spasm and spasticity, or disorders of thecardiovascular system, that is, use as an antihypertensive.

The invention further relates to a process of preparing the compounds ofthe invention represented by Formula (I) by converting the appropriate,substituted diamine to the 2-amino-4-phenyl (or5-phenyl)-1,4,5,6-tetrahydropyrimidine. This, in turn, can be convertedto the corresponding 2-alkoxycarbonylamino compound or the2-alkylcarbonylamino compound. Alternatively, the diamine can beconverted directly to the 2-alkoxycarbonylamino compound.

A more complete discussion of the preferred embodiments is foundhereinafter.

FURTHER DESCRIPTION AND PRESENTLY PREFERRED EMBODIMENTS COMPOUNDS

The broadest aspect of this invention is a compound selected from thoserepresented by the formula ##STR2## wherein

A is hydrogen, RC(O)-- or ROC(O)--;

R is alkyl of one through six carbon atoms;

R¹ is hydrogen or alkyl of one through six carbon atoms;

X is fluoro, chloro, bromo, iodo, alkoxy of one through four carbonatoms, benzyloxy, hydroxy, alkyl of one through four carbon atoms,alkylthio of one through four carbon atoms, alkyl sulfinyl of onethrough four carbon atoms, alkyl sulfonyl of one through four carbonatoms, trifluoromethyl or hydrogen;

Y is hydrogen or is the same as X;

the phenyl substituent carrying the X and Y is at the 4- or 5-positionof the tetrahydropyrimidine ring when R¹ is hydrogen or is at the5-position, when R¹ is alkyl;

and the pharmaceutically acceptable salts thereof.

A subgroup of this invention includes the compounds represented byFormula (I) wherein

A is hydrogen, RC(O)-- or ROC(O)--;

R is methyl or ethyl;

R¹ is hydrogen, methyl or ethyl;

X is hydrogen, fluoro, chloro, methoxy, ethoxy, methyl, ethyl orhydroxy;

Y is hydrogen or the same as X; and

the pharmaceutically acceptable salts thereof.

The broadest aspect of the invention can be further subdivided intosubgroups such as amines, as shown in Formula (II), amides as shown inFormula (III), or carbamates as shown in Formula (IV).

The amines of this invention include the group compounds represented bythe formula ##STR3## wherein

X is fluoro, chloro, bromo, iodo, alkoxy of one through four carbonsatoms, benzyloxy, hydroxy, alkyl of one through four carbon atoms,alkylthio of one through four carbon atoms, alkyl sulfinyl of onethrough four carbon atoms, alkyl sulfonyl of one through four carbonatoms, trifluoromethyl or hydrogen;

Y is hydrogen or is the same as X;

R¹ is hydrogen or alkyl of one through six carbon atoms;

the phenyl substituent carrying the X and Y is at the 4- or 5-positionof the tetrahydropyrimidine ring when R¹ is hydrogen or is at the5-position when R¹ is alkyl;

A preferred subgroup of this class of compounds includes the compoundsrepresented by Formula (II) wherein X is fluoro, chloro, methoxy,ethoxy, hydroxy, methyl, ethyl or hydrogen; Y is hydrogen or is same asX; and R¹ is hydrogen, methyl or ethyl. Of the preferred subgroup, thecompounds wherein X is fluoro, chloro or hydrogen; Y is hydrogen or thesame as X; and R¹ is hydrogen or methyl are particularly preferred.

Typical specific illustrations of the amines of this invention are setforth in the Examples hereafter.

The amides of this invention include the compounds represented by theformula ##STR4## wherein

X is fluoro, chloro, bromo, iodo, alkoxy of one through four carbonatoms, benzyloxy, hydroxy, alkyl of one through four carbon atoms,alkylthio of one through four carbon atoms, alkylsulfinyl of one throughfour carbon atoms, alkylsulfonyl of one through four carbon atoms,trifluoromethyl or hydrogen;

Y is hydrogen or is the same as X;

R is alkyl of one through six carbon atoms;

R¹ is hydrogen or alkyl of one through six carbon atoms; and

the phenyl substituent carrying the X and Y is at the 4- or 5-positionof the tetrahydropyrimidine ring when R¹ is hydrogen or is at the5-position, when R¹ is alkyl;

A preferred subgroup of this group of compounds includes thoserepresented by Formula (III) wherein X is fluoro, chloro, methoxy,ethoxy, hydroxy, methyl, ethyl or hydrogen; Y is hydrogen or is the sameas X; R is methyl or ethyl; and R¹ is hydrogen, methyl or ethyl.

Of the preferred subgroup, those compounds particularly preferredinclude the compounds of Formula (III) wherein X is fluoro, chloro orhydrogen; Y is hydrogen or is the same as X; R¹ is hydrogen or methyland R is methyl.

Typical specific illustrations of the amides of this invention are setforth in the Examples hereafter.

The carbamates of this invention are represented by the compounds of theFormula ##STR5## wherein

X is fluoro, chloro, bromo, iodo, alkoxy of one through four carbonatoms, benzyloxy, hydroxy, alkylthio of one through four carbon atoms,alkylsulfinyl of one through four carbon atoms, alkylsulfonyl of onethrough four carbon atoms, trifluoromethyl or hydrogen;

Y is hydrogen or is the same as X;

R is alkyl of one through six carbon atoms,

R¹ is hydrogen or alkyl of one through six carbon atoms; and

the phenyl substituent carrying the X and Y is at the 4- or 5-positionof the tetrahydropyrimidine ring when R¹ is hydrogen or is at the5-position, when R¹ is alkyl.

A preferred subgroup of this group of compounds includes thoserepresented by Formula (IV) wherein X is fluoro, chloro, methoxy,ethoxy, hydroxy, methyl, ethyl or hydrogen; Y is hydrogen or is the sameas X; R¹ is hydrogen, methyl or ethyl; and R is methyl or ethyl. Of thissubgroup, those particularly preferred are the compounds represented byFormula (IV), wherein X is fluoro, chloro, methoxy, ethoxy, methyl,ethyl or hydrogen; Y is hydrogen or is the same as X; R¹ is hydrogen,methyl or ethyl; and R is methyl or ethyl.

Typical specific illustrations of the carbamates of this invention areset forth in the Examples hereafter.

The compounds of this invention are optionally substituted at the1-position of the tetrahydropyrimidine ring with an alkyl group; at the2-position with an amino (NH₂), an alkyl carbonylamino (--NHC(O)R) oralkoxycarbonylamino (--NHC(O)OR); and at the 4- or 5-position with aphenyl or substituted phenyl. Where the phenyl substitution is at the5-position with no substitution at the 1-position, the compounds are notoptically active because of tautomerism, i.e. there is an equilibriumbetween the two linkage isomers. However, once the position of thedouble bond is fixed by the alkyl substitution at the 1-position, thecompounds are optically active due to the asymmetrical atom at the fiveposition. If on the other hand, the phenyl is substituted at the4-position, the compounds of the invention have an asymmetric carbonatom at the 4-position of the tetrahydropyrimidine ring and thus existas optically active enantiomers, i.e. (+) and (-) compounds. The aboveFormulas (I), (II), (III) and (IV) are intended to represent therespective individual (+) and (-) optical enantiomers as well asmixtures thereof, and accordingly the individual enantiomers as well asmixtures thereof (e.g. racemic mixtures) are encompassed within thescope of the invention.

The compounds of the invention will be named herein, for purposes ofconvenience, as follows:

A. 4-phenyl substituted compounds

2-amino-4-(substituted phenyl)-1,4,5,6-tetrahydropyrimidine;

2-alkylcarbonylamino-4-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

2-alkoxycarbonylamino-4-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

B. 5-phenyl substituted compounds

2-amino-5-(substituted phenyl)-1,4,5,6-tetrahydropyrimidine;

1-alkyl-2-amino-5-(substituted phenyl)1,4,5,6-tetrahydropyrimidine;

2-alkylcarbonylamino-5-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

1-alkyl-2-alkylcarbonylamino-5-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

2-alkoxycarbonylamino-5-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

1-alkyl-2-alkoxycarbonylamino-5-(substitutedphenyl)-1,4,5,6-tetrahydropyrimidine;

Also included within the scope of the invention are pharmaceuticallyacceptable salts of each of the above subgroups compounds.

Pharmaceutically acceptable salts include those salts of the parentcompound which do not significantly adversely affect the pharmaceuticalproperties (e.g. toxicity, effectiveness, etc.) of the parent compoundand are conventionally used in the pharmaceutical art. Thepharmaceutically acceptable salts of the present invention arepharmaceutically acceptable hydrogen-anion addition salts of thecompounds of Formula (I), (II), (III) and (IV). Suitablepharmaceutically acceptable hydrogen-anion addition salts include(expressed with respect to the anion), for example, inorganic salts suchas, for example, chloride, bromide, iodide, sulfate, phosphate, nitrate,and the like, or organic salts such as, for example, acetate, benzoate,lactate, propionate, butyrate, valerate, tartrate, maleate, fumarate,citrate, succinate, tosylate, ascorbate, palmitate, glyconate, adipate,and the like.

The preferred pharmaceutically acceptable salts are the hydrochloride,hydrobromide, nitrate, maleate and citrate, and correspondingly thepreferred and particularly preferred salts are the corresponding saltsof the groups of the preferred and particularly preferred compoundsdescribed above.

Utility and Administration

The compounds of the invention are useful as agents for treating,palliating, or preventing undesirable conditions, in mammals, involvingthe central nervous system such as depression, anxiety, convulsions,centrally induced skeletal muscle spasms or spasticity disorders. Thus,the compounds of the invention are useful as antidepressants, anxiolyticagents, anticonvulsants, antispasmotics, or antispasticity agents.

Initial determination of the spectrum of psychotropic activity, inmammals, for a given compound is obtained by applying routineexperimental procedures. Antidepressant activity is initially determinedusing the methods discussed in Askew, Life Sciences, Vol. 2, p. 725(1963) and Vernier et al, Fed. Proc., Vol. 21, p. 419 (1962). Depressantor tranquilizing activity (antianxiety agent) is initially determinedusing methods discussed by Irwin in Animal and Clinical PharmacologicalTechnique in Drug Evaluation edited by J. H. Nodine et al, pp. 36-54,Year Book Medical Publishers, Inc., Chicago (1964). For anticonvulsantactivity the method used is described by Swinyard, J. of Amer. Phar.Assoc., Scientific Edition, Vol. 38, p. 201 (1949). For centrally actingskeletal muscle relaxant activity based on polysynaptic transmissioninhibition (antispasmotic) the method used is set forth in King andUnna, "The Action of Mephenesin and Other Interneuron Depressants on theBrain Stem", J. Pharmacol. Exp. Ther., Vol. 111, p. 293 (1954); Barnettand Fiore, European Journal of Pharmacology, Vol. 13, p. 239 (1971);Kamijo and Koelle, Proceedings of the Society for Experimental Biologyand Medicine, Vol. 88, pp. 565-568 (1955).

The compounds of the invention are also useful in the treatment andpalliation of cardiovascular abnormalities in mammals, particularly inthe treatment of hypertension in mammals. Thus a therapeuticallyeffective amount for hypertension will be an amount sufficient to lowerthe blood pressure in the animal being treated.

In general, the dosage will be an amount effective to achieve thedesired results. The preferred dosage depends upon the particularsubject and disorder being treated and can vary within wide limits suchas, for example, between 0.001 and 50 mg. per kg. of body weight perday, preferably between 0.01 and 10 mg/kg. Generally, where thecompounds are administered as antidepressants, they can be administeredin the same manner as imipramine and preferably are administered at arate of less than about 10 mg/kg per day and preferably less than 5mg/kg. Where the compounds are administered as anticonvulsants, they arebest administered prophylactically to prevent or reduce the occurrenceand/or severity of convulsions in mammals which are subject toconvulsions which are etiopathic to the central nervous system. When thecompounds of this invention are administered for the treatment ofcardiac disorders such as hypertension, dosages (preferably oral) ofabout from 0.6-6.0 mg. per kg. of body weight are sufficient.

The compounds can be administered orally, rectally or parenterally (forexample, by intravenous, intraperitoneally or intramuscular injection).The compounds are typically administered as pharmaceutical compositionscomprising at least one compound of the invention and at least onesuitable pharmaceutical excipient. Where the compounds are administeredparenterally, they will, of course, be administered in liquid dosageforms, whereas when administered orally or rectally, they can beadministered in either solid or liquid forms. Typically, the dosageforms comprise the compound and a pharmaceutically acceptable excipientsuch as a carrier, preferably formulated in unit dosage form tofacilitate the simple administration of precise dosages. The dosage formcan optionally contain other compatible medicaments and excipients suchas preservatives, emulsifying agents and wetting agents and bufferingagents. Liquid dosage forms include, for example solutions, suspensions,emulsions, syrups, elixirs, etc. Liquid carriers include, for example,water, saline solution, etc. Solid dosage forms include, for example,tablets, powders, capsules, pills, etc. Suitable solid carriers include,for example, pharmaceutical grades of starch, lactose, sodium saccharin,sodium bisulfite and the like, and conventional suppository carriers,e.g. polyethylene glycol, polysorbate, stearic acid, diglycol stearate,carbowax, etc.

Thus, the compounds may be prepared as pills such as capsules or tabletseach having about 10-200 mg per pill.

Definitions

The following terms, as used hereinabove and below, have the followingmeaning unless expressly stated to the contrary. The term alkyl includesboth straight chain and branched chain alkyls having the number ofcarbon atoms indicated. For example alkyl of one through four carbonatoms include, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl,n-butyl and the like. Alkyl of one through six includes the foregoing aswell as amyl, hexyl and the like. The term alkoxy of one through fourcarbon atoms can be defined as the group OR' wherein R' is alkyl of onethrough four carbon atoms.

The term "room temperature" or "ambient temperature" refers to about 20°Centigrade and all temperatures and temperature ranges refer to degreesCentigrade. All percents refer to weight percents and the termequivalent mole amount refers to an amount stoichiometrically equivalentto the other reactant in the reaction referred to.

PROCESS OF THE INVENTION A. 5-Phenyl-1,4,5,6-tetrahydropyrimidines

The symmetrical compounds of this invention, namely, the 5-(optionallysubstituted phenyl)-1,4,5,6-tetrahydropyrimidines, are prepared byconverting a suitable propane diamine of Formula (D) in ReactionSequence 1 to the 2-aminotetrahydropyrimidine of Formula (II¹), or thecarbamate of Formula (IV¹). The aminotetrahydropyrimidine (II¹) isconverted to the carbamate (IV¹) or the amide of Formula (III¹).##STR6##

The overall process is set forth in Reaction Sequence 1 using as thestarting material an appropriately substituted benzyldehyde of FormulaA, where X and Y are as hereinbefore defined. Where X is hydroxy,however it is preferably first converted to benzyloxybenzaldehyde whichis reacted as shown in Reaction Sequence 1 and finally the benzyloxy isconverted to the hydroxy by hydrogenolysis.

The benzaldehyde Formula (A) is reacted with cyanoacetic acid at atemperature of from about 30° C. to about 120° C. in a suitable solvent.Preferably the temperature is from about 50° C. to about 100° C. Thesolvent can be any solvent in which the reaction readily takes place butis preferably a cyclic amine such as pyridine. Also present is a smallamount of a stronger base such as morpholine, piperidine, piperazine,diazabicyclononine, etc. Preferably this base is piperidine. Thecyanoacetic acid reacts with the benzaldehyde according to theprinciples discussed in Chem. Ber., Vol. 95, pages 195-198, (1962), byChiemenz and Engelhard. That reference is incorporated herein byreference. The product of this reaction is the correspondingphenylglutaronitrile shown in Reaction Sequence 1 as Formula (B).

The compound of Formula (B) is then treated with an aqueous acid to formthe corresponding 3-phenylglutaramide of Formula (C). The acid may beany suitable inorganic mineral acid such as hydrochloric or sulfuric.Preferably sulfuric acid is employed. This reaction can be carried outat temperatures from about 5° C. to about 50° C., but is preferablycarried out at about room temperature. Once the reaction is complete,excess acid is neutralized with a suitable base such as ammoniumhydroxide and the resulting solid precipitate is collected byfiltration, centrifugation or the like. Alternatively, any other knownmethods of formation of amides from nitriles can be employed. Forexample, refluxing the nitrile of Formula (B) with aqueous base resultsin the corresponding amide. The addition of hydrogen peroxideaccelerates the hydration of nitriles in alkaline solutions, thushydrogen peroxide with a suitable base such as sodium carbonate, sodiumhydroxide, potassium hydroxide, magnesium hydroxide or the like can beused with success. This is further discussed in Organic Chemistry, 2ndEd., Cram and Hammond, p. 307, McGraw Hill Book Company, 1964. Inaddition the process may be performed by adapting the method describedby Murray and Cloak in Journal of the American Chemical Society, Vol.56, pages 2749-2751 (1934). These references are incorporated herein byreference.

The amide of Formula (C) in turn is readily converted into the2-phenyl-1,3-propanediamine of Formula (D) by adaptation of the Hoffmanrearrangement or any of the other known methods for the preparation ofamines from amides that proceed with the loss of one carbon, forexample, by treatment with lead tetracetate. In the Hoffmanrearrangement, the unsubstituted amide is reacted with sodiumhypobromite (or aqueous sodium hydroxide and bromine) at lowtemperatures of -20° to about 10° C. The reaction takes place readily atlow temperatures of about -10° to about 10° C. with increased heating asthe reaction progresses, the reaction reaching completion at about 50°to 100° C., preferably 70° C. The reaction is discussed in Cram andHammond's Organic Chemistry, ibid, p. 490 and in S. Simons, J. ORG.CHEM. 38, 414 (1973). The references are incorporated herein byreference.

Once the diamine of Formula (D) is obtained it can be converted into the2-amino-1,4,5,6-tetrahydropyrimidine compound or Formula (II¹) or the2-alkoxycarbonylamino-1,4,5,6-tetrahydropyrimidine compound. The2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidino compounds are prepared byadopting methods known in the art to this particular process. Forexample, the method set forth in Matier, et al, J. of MED. CHEM. 16, No.8, 901-908 (1973), has been found to be particularly useful. In thiscase the diamine as the free base is dissolved in a suitable solventsuch as methanol and a solution of cyanogen bromide in an inert solventsuch as methanol is added to the solution. Generally the reaction willbe complete in less than 5 hours at a temperature of about 10° to about50° C., preferably about 20° to 30° C. This method results in the2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine hydrobromide which is thencrystallized from a suitable solvent such as methanol andisopropylether.

This compound is readily converted into the amide by reacting with asuitable acid chloride, anhydride, ester or the acid itself in thepresence of an activating agent such as dicyclohexylcarbodiimid orcarbonyldiimidazole. Alternatively, a carboxylic acid derivative, forexample tetraacylglycolrils can be used. For preparations and reactionsof tetraacylglycolurils see D. Kuhling, Ann.Chem. 1973, 263 and C. Haseand D. Kuhling, Ann.Chem. 1975, 95.

The 2-alkoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine isreadily prepared by adapting known methods to the particular compoundsat hand. See for example U.S. Pat. No. 4,088,771 to Roszkowski et al,which is incorporated herein by reference.

The diamine of formula (D) is reacted with a compound represented by theformulas ##STR7## where Z is hydrogen or COOR, R is lower alkyl of onethrough six carbon atoms and R² is alkyl of one through five carbonatoms.

This reaction can be conveniently effected by treating the diamine ofFormula (D), or typically an acid salt thereof (e.g. the dihydrochloridesalt), with the starting material of formula L or L' having the desiredR substituent, in a suitable solvent. Typically, the reaction isconducted under alkaline to slightly acid conditions, preferablyessentially neutral. Where an acid salt of the diamine of Formula (D) isused, a sufficient amount of an inorganic or organic base is added tothe reaction mixture either before or after the addition of one or bothof the reactants to neutralize all or part of the acid salt moiety.Suitable bases which can be used include, for example, alkali metalcarbonate, or bicarbonates, acetates, for example, sodium carbonate,potassium carbonate, sodium bicarbonate, sodium acetate, alkali metallower alkoxides, for example, sodium methoxide, potassium methoxide,sodium t-butoxide, lithium methoxide, and the like, alkali metal andalkali earth hydroxides, for example, sodium hydroxide, potassiumhydroxide, calcium hydroxide, and the like, and mixtures thereof.Suitable organic bases include, for example, pyridine, triethylamine,diazabicyclononane, and the like or mixtures thereof.

Conveniently, the solvent in which the reaction is carried out is amixture of water and one or more inert organic solvents. Suitable inertorganic solvents which can be used include, for example, methanol,ethanol, isopropanol, diethyl ether, chloroform, benzene and the likeand mixtures thereof. The reaction is carried out at temperatures in therange of about from 10° to 100° C., preferably about from 50° to 75° C.,for about from 1/2 hour to 14 days. Typically, a mole ratio of aboutfrom 0.5 to 2, preferably about 1 mole of the diamine of Formula (D) isused per mole of starting material of Formula (L) or (L'). However,temperatures, reaction times, and mole ratios both above and below theseranges can be used. Optimum conditions will, of course, vary with theparticular reactants and solvents, and can be determined by routineexperimentation. The products of Formula (IV) can be separated from theproduct reaction mixture and further purified by conventionalprocedures, e.g. filtration, washing, evaporation, crystallization andthe like. Non-limiting illustrations of detailed separation andpurification procedures can be had by reference to the Examples setforth hereinbelow.

The starting materials of Formulas (L) and (L') are known compounds andcan be prepared according to known procedures such as those set forth inJapanese Application No. 50012087 or by obvious modifications of suchprocedures. The compounds of Formula (C) can be used either as therespective mono- (Z is H) or bis- (Z is COOR) or as a mixture of themono- and bis-compounds. Conveniently, the compound of Formula (L) isprepared as a mixture of the mono- (Z is H) and bis (Z is COOR) and themixture then used in the aforedescribed reaction without separation ofthe mono- and bis-products.

In a further process embodiment, the compounds of the inventionrepresented by Formula (IV¹) are prepared by treating the diamine ofFormula (D) with a compound of the general formula ##STR8## wherein R isas defined hereinabove and M and P independently are chlorine, loweralkoxy or lower alkylthio. The term lower alkoxy or lower alkylthiorefers to alkoxy or alkylthio groups having an alkyl group from onethrough six carbon atoms which may be branched or straight chainattached to an oxygen or sulfur atom. The reaction preferably is carriedout in the presence of a suitable organic or inorganic base, such astriethylamine, pyridine, sodium hydroxide, sodium bicarbonate, or sodiumcarbonate at 0° to 100° C., preferably at 0° to 50° C.

If one of M or P is halogen and the other of M or P is lower alkoxy orlower alkylthio the reaction is first started in the presence of a baseand completed at a pH of 2 to 8 between 0° to 150° C., preferably 20° to120° C.

If both M and P are lower alkoxy or lower alkylthio, the reaction iscarried out at 0° to 150° C., preferably 30° to 120° C., optionally in asolvent such as a lower alkanol, acetonitrile diluted acetic acid,ethylene glycol, tetrahydrofurane, dioxane, benzene, toluene,halogenated hydrocarbon, water, or the like. It is advantageous to usesolvents which contain water. The pH range should be between 2 and 8preferably between 2 and 5.

The compounds of Formula (L") are known compounds and can be prepared inaccordance with the procedures described in German OLS No. 2438120.

In still a further modification the compounds of the invention can beprepared by treating the diamine of Formula (D) with a compound of thegeneral formula

    ROOC--NHCN

wherein R is as defined above. The reaction conditions are the same asapplied with the compounds of the Formula (L") with M and P both beinglower alkoxy or lower alkylthio. These compounds may also be prepared bymethods described in German OLS No. 2438120.

In a further embodiment, the compounds of this invention are prepared byreacting the compound of Formula (II') with a carbonate of the formula##STR9## wherein R is alkyl of one through six carbon atoms. Thisreaction can be conveniently effected at a suitable temperature bytreating the compound of formula (II), or typically an acid saltthereof, e.g. the hydrobromide salt, with the carbonate having thedesired R substituent in an inert solvent or by using an excess of thecarbonate as the solvent. A suitable temperature for the reaction willbe about 20° C. to about 120° C., preferably about 70° C. to about 100°C. Typically where an acid salt of compound (II') is used as thestarting material, the salt is treated before addition of the carbonatewith a sufficient amount of an inorganic or organic base to liberate thefree base. Suitable bases which can be used include, for example, alkalimetal carbonates, alkali metal lower alkoxides, for example, sodiummethoxide, potassium methoxide, sodium t-butoxide, lithium methoxide,and the like, alkali metal and alkali earth hydroxides, for examplesodium hydroxide, potassium hydroxide, calcium hydroxide, and the like,and mixtures thereof. Suitable organic bases include, for example,pyridine, triethylamine, diazabicyclononane, and the like and mixturesthereof. Suitable inert organic solvents which can be used include, forexample, toluene, dioxane, and the like and mixtures thereof.

The compounds of the invention can also be prepared by reacting the2-amine of Formula (II¹) with an alkyl chloroformate (ClCOOR) having thedesired R-alkyl substituent in a suitable inert organic solvent; e.g.acetone. This reaction takes place at about -20° C. to about 20° C.,preferably about -5° C. to 5° C.

The 5-phenyl-1,4,5,6-tetrahydropyrimidines of this invention which aresubstituted with an alkyl at the 1-position are prepared from thecorresponding N-alkyl-2-phenyl-1,3-propanediamine according to ReactionSequence 2. ##STR10##

In Reaction Sequence 2, the starting material, ethylene glycol acetal ofatropaldehyde of Formula (E) (a known material, see E. Elkik, Bull. Soc.Chim. Fr, 1968(1), 283) is first hydrolyzed by reacting in a weaklyacidic aqueous solvent at temperatures of about 25° C. to about 100° C.,preferably about 65°-75° C. Any organic or inorganic acid can be usedwith oxalic acid being preferred. The reaction is carried out in asuitable polar, organic solvent which is miscible with water. The loweralcohols such as methanol, ethanol, isopropanol, and the like areuseful, with ethanol being preferred. The hydrolysis can be followed bygas chromatography and is usually complete after about forty minutes ata reaction temperature of 70°-80° C. The liberated atropaldehyde (F) canbe isolated (See E. Elkik, supra) or can be reacted in situ by adding anN-alkylhydrazine directly to the hydrolysis mixture. This latterprocedure is preferred to avoid the difficulties inherent in thepolymerization of atropaldehyde (see E. Elkik, supra). Once the acetalis hydrolyzed a suitable N-alkylhydrazine is added and reacted attemperatures of about 10° C. to about 40° C., preferably ambienttemperature. This results in a product represented by Formula (G)wherein R is alkyl of one through six carbon atoms, depending on theN-alkylhydrazine. For example, N-methylhydrazine, N-ethylhydrazine,N-isopropylhydrazine, N-t-butylhydrazine and N-n-hexylhydrazine resultsin a compound of Formula (G) wherein R is methyl, ethyl, isopropyl,t-butyl and n-hexyl, respectively. The pyrrazoline of Formula (G) isreduced, for example by catalytic hydrogenation, to the N-alkylpropanediamine of Formula (D²). The compound of Formula (D²) is then convertedto the amino pyrimidine (II²), amide (III²) or carbamate (IV² )according to procedures discussed hereinbefore.

B. 4-Phenyl-1,4,5,6-tetrahydropyrimidines

The preparation of the 2-amino-, 2-amido- or2-alkoxycarbonylamino-4-(optionally substitutedphenyl)-1,4,5,6-tetrahydro- pyrimidines is shown in Reaction Sequence 3.##STR11##

In this case the starting materials represented by Formula (H) aredifferent but the intermediate steps from the phenylglutaranitrile ofFormula (J) are similar to those set forth hereinbefore for the5-phenyl-1,4,5,6-tetrahydropyrimidines and the reaction conditions forthose steps as previously defined apply here. The preparation of thecompound of Formula (J) occurs as discussed by R. Bertocchio and J.Dreux, Bull. Soc. Chem. Fr. 1962, 1809-1813. In the preparation of the2-phenylglutaronitrile of Formula (J) the appropriate phenylacetonitrileof Formula (H) is reacted with acrylonitrile (CH₂ ═CHCN) at temperaturesof about 30° to 100° C., preferably under reflux for less than 5 hours.Generally, the phenylacetonitrile will be in substantial molar excessover the acrylonitrile and will act as a solvent for the reactionmixture. However, other solvents which are suitable and inert towardsthe reaction can be used such as toluene. The mixture that resultsconsists mainly of unreacted phenylacetonitrile (H),phenylglutaronitrile (J) and the pentane tricarbonitrile (K). The threenitriles are separated by vacuum distillation and recrystallization.

The 2-phenylglutaronitrile (J) is then converted to the compoundrepresented by Formula (M) which in turn is converted to the diamine ofFormula (N) which then is converted to the desired products of Formulas(II³), (III³) or (IV⁴). The reaction conditions required to convert the2-phenylglutaranitrile of Formula (J) to the compounds of this inventionare essentially the same as the conditions discussed in the section forthe preparation of the 5-substituted 1,4,5,6-tetrahydropyrimidines asdiscussed before.

An alternative route to the preparation of the1-phenyl-1,3-propanediamine is set forth in Reaction Sequence 4.##STR12##

In this sequence, the starting material is the appropriately substitutedbenzonitrile (O) and the reaction to the β-aminocinnamonitrile (Q) isessentially as that set forth in Chem. Ber., 82, 254 (1949) by Dornow etal, which is incorporated herein by reference. In this ReactionSequence, the benzonitrile is reacted with acetonitrile to give theβ-aminocinnamonitrile represented by Formula (O) which in turn isreduced to give the 1-phenyl-1,3-propanediamine, which is then convertedto a compound of Formula (II⁴), (III⁴), or (IV⁴) as discussedhereinbefore.

The respective optical isomers of formulas II² -II⁴, III² -III⁴, and IV²-IV⁴ can be conveniently prepared by using the corresponding opticallyactive isomer starting material of Formulas (D²), (K), (N), etc. Theoptically active isomer starting material can be obtained by resolutionof the corresponding dl mixture by applying conventional resolutionprocedures. Note for example the procedure described in Ann. Chem., Vol.494, page 143 (1932). Also see "Tables of Resolving Agents and OpticalResolutions," Samuel H. Wilen, U. of Notre Dame Press (1972), pp.159-181 and "Stereochemistry of Carbon Compounds" by E. Eliel,McGraw-Hill, 1962, Chap. 4.

The pharmaceutically acceptable salts of the compounds of the invention(including Formulas II² -II⁴, III² -III⁴, and IV¹ -IV⁴ racemic mixturesand separate optical isomers) can be conveniently prepared by treatingthe corresponding free base of Formula (I), of the invention, with anacid or via other conventional procedures such as, for example, ionexchange. The free base of Formula (I) may be obtained from thepharmaceutically acceptable salt by treating said salt with aconventional organic or inorganic base such as one employed to liberatea free base from the corresponding acid salt as described hereinbefore.

A further understanding of the invention can be had from the followingnon-limiting preparations and examples, wherein, unless stated to thecontrary, racemates are used as starting materials and correspondingracemic mixtures are obtained as products.

PREPARATION A: 3-phenylglutaronitriles (Reaction Sequence 1)

1. 3-(2,6-dichlorophenyl)glutaronitrile

A solution consisting of 31.5 grams (g) of 2,6-dichlorobenzaldehyde, 39g of cyanoacetic acid and 2.5 milliliters (ml) of piperidine in 100 mlof pyridine is heated on a steambath for 7 hours. The initial rapidevolution of carbon dioxide gradually diminishes over the reaction time.Most of the solvent is removed under reduced pressure and the residue isdissolved in about 400 ml of benzene. The solution is washed three timeswith water, three times with dilute sodium bisulfite, again with water,and finally with saturated sodium bicarbonate. The solvent is removedunder vacuum and the residue is recrystallized once from 50 ml ofmethanol and once more from 50 ml of isopropanol to give 12.3 g of3-(2,6-dichlorophenyl)glutaronitrile having a melting point (mp) of104°-6° C.

2. Similarly, by following in principle the procedure of Part 1 of thisPreparation but substituting an appropriate benzaldehyde for2,6-dichlorobenzaldehyde, other 3-phenylglutaronitriles are preparedsuch as

3-phenylglutaronitrile, boiling point (bp) 128°-134° C. at 0.02 mm;

3-(2-chlorophenyl)glutaronitrile, bp about 150° C. at 0.02 mm;

3-(3-chlorophenyl)glutaronitrile;

3-(4-chlorophenyl)glutaronitrile;

3-(2-fluorophenyl)glutaronitrile;

3-(3-fluorophenyl)glutaronitrile;

3-(4-fluorophenyl)glutaronitrile, bp 130°-140° at 0.005 mm;

3-(2-bromophenyl)glutaronitrile;

3-(3-bromophenyl)glutaronitrile, mp 94°-96° C.;

3-(4-bromophenyl)glutaronitrile;

3-(2-iodophenyl)glutaronitrile;

3-(3-iodophenyl)glutaronitrile;

3-(4-iodophenyl)glutaronitrile;

3-(2,3-dichlorophenyl)glutaronitrile;

3-(2,4-dichlorophenyl)glutaronitrile, mp 76°-78° C.;

3-(3,4-dichlorophenyl)glutaronitrile;

3-(3,5-dichlorophenyl)glutaronitrile;

3-(2,5-dichlorophenyl)glutaronitrile;

3-(2,3-didifluorophenyl)glutaronitrile;

3-(2,4-difluorophenyl)glutaronitrile;

3-(3,4-difluorophenyl)glutaronitrile;

3-(2,5-difluorophenyl)glutaronitrile;

3-(2,6-difluorophenyl)glutaronitrile;

3-(3,5-difluorophenyl)glutaronitrile;

3-(2,6-dibromophenyl)glutaronitrile;

3-(2,4-dibromophenyl)glutaronitrile;

3-(3,5-dibromophenyl)glutaronitrile;

3-(2,4-diiodophenyl)glutaronitrile;

3-(2,6-diiodophenyl)glutaronitrile; and the like.

3. 3-(3-methoxyphenyl)glutaronitrile

A solution consisting of 25 g of m-anisaldehyde, 47 g of cyanoaceticacid and 3 ml of piperidine in 120 ml of pyridine is placed in asuitable reaction vessel and kept in a 110° oil-bath for 22 hours. Mostof the solvent is removed under reduced pressure and the remaining oilis dissolved in about 400 ml of toluene. The solution is washedsequentially with equal volumes of water, 10% hydrochloric acid andsaturated sodium bicarbonate. The washed solution is then concentratedunder vacuum and the residue is distilled to give 20.7 g of3-(3-methoxyphenyl)glutaronitrile, bp 146°-153° at 0.01 mm.

4. Similarly, by following in principle the procedure of Part 3 of thispreparation but substituting other substituted benzaldehydes form-anisaldehyde, other 3-(substituted phenyl)glutaronitriles can beprepared, such as

3-(2-methoxyphenyl)glutaronitrile;

3-(4-methoxyphenyl)glutaronitrile;

3-(2-ethoxyphenyl)glutaronitrile;

3-(3-ethoxyphenyl)glutaronitrile;

3-(4-ethoxyphenyl)glutaronitrile;

3-(2-propoxyphenyl)glutaronitrile;

3-(3-propoxyphenyl)glutaronitrile;

4-(4-propoxyphenyl)glutaronitrile;

3-(4-butoxyphenyl)glutaronitrile;

3-(2-benzyloxyphenyl)glutaronitrile;

3-(3-benzyloxyphenyl)glutaronitrile;

3-(4-benzyloxyphenyl)glutaronitrile, m.p. 140°-143°;

3-(2-methylphenyl)glutaronitrile;

3-(3-methylphenyl)glutaronitrile;

3-(4-methylphenyl)glutaronitrile, bp 124°-130° C./0.02 mm,

3-(2-ethylphenyl)glutaronitrile;

3-(3-ethylphenyl)glutaronitrile;

3-(4-ethylphenyl)glutaronitrile;

3-(2-isopropylphenyl)glutaronitrile;

3-(3-isopropylphenyl)glutaronitrile;

3-(4-isopropylphenyl)glutaronitrile, bp about 180° C./0.05 mm;

3-(2-trifluoromethylphenyl)glutaronitrile

3-(3-trifluoromethylphenyl)glutaronitrile;

3-(4-trifluoromethylphenyl)glutaronitrile;

3-(2-methylthiophenyl)glutaronitrile;

3-(4-methylthiophenyl)glutaronitrile;

3-(2-ethylthiophenyl)glutaronitrile;

3-(4-ethylthiophenyl)glutaronitrile;

3-(2-butylthiophenyl)glutaronitrile;

3-(3-butylthiophenyl)glutaronitrile;

3-(4-methylsulfinylphenyl)glutaronitrile;

3-(4-ethylsulfonylphenyl)glutaronitrile;

3-(2,4-dimethoxyphenyl)glutaronitrile;

3-(2,6-diethoxyphenyl)glutaronitrile;

3-(3,4-dibenzoyloxyphenyl)glutaronitrile;

3-(3,5-diethylthiophenyl)glutaronitrile;

3-(2,6-dimethylsulfinylphenyl)glutaronitrile;

3-(2,6-dimethylsulfonylphenyl)glutaronitrile; and the like.

PREPARATION B: 3-Phenylglutaramides (Reaction Sequence 1)

1. 3-(2,6-dichlorophenyl)glutaramide

Twelve and three-tenths (12.3) of 3-(2,6-dichlorophenyl)glutaronitrile,prepared according to Preparation A, Part 1, is dissolved in a mixtureof 70 ml of concentrated sulfuric acid and 3 ml of water. This solutionis allowed to stand for 2 days at room temperature and then poured overcrushed ice and is neutralized with ammonium hydroxide. The solidprecipitate is collected, washed with water and dried under vacuum togive 13.8 g of 3-(2,6-dichlorophenyl)glutaramide, mp 221°-225°.

2. Similarly, by following the procedure of Part 1 of this preparationbut substituting other suitable 3-phenylglutaronitriles (such as thoseset forth in Preparation A, Parts 2 or 5), for3-(2,6-dichlorophenyl)glutaronitrile, other corresponding3-phenylglutaramides are obtained such as

3-phenylglutaroamide, melting point 183°-184° C.;

3-(2-chlorophenyl)glutaramide, mp 189° C.;

3-(3-chlorophenyl)glutaramide;

3-(4-chlorophenyl)glutaramide;

3-(2-fluorophenyl)glutaramide;

3-(3-fluorophenyl)glutaramide;

3-(4-fluorophenyl)glutaramide, mp 194°-196° C.;

3-(2-bromophenyl)glutaramide;

3-(3-bromophenyl)glutaramide, mp 168°-170° C.;

3-(4-bromophenyl)glutaramide;

3-(2-iodophenyl)glutaramide;

3-(3-iodophenyl)glutaramide;

3-(4-iodophenyl)glutaramide;

3-(2,3-dichlorophenyl)glutaramide;

3-(2,4-dichlorophenyl)glutaramide, mp 194°-196° C.;

3-(3,4-dichlorophenyl)glutaramide;

3-(3,5-dichlorophenyl)glutaramide;

3-(2,5-dichlorophenyl)glutaramide;

3-(2,3-difluorophenyl)glutaramide;

3(2,4-difluorophenyl)glutaramide;

3-(3,4-difluorophenyl)glutaramide;

3-(2,5-difluorophenyl)glutaramide;

3-(2,6-difluorophenyl)glutaramide;

3-(3,5-difluorophenyl)glutaramide;

3(2,6-dibromophenyl)glutaramide;

3-(2,4-dibromophenyl)glutaramide;

3-(3,5-dibromophenyl)glutaramide;

3-(2,4-diiodophenyl)glutaramide;

3-(2,6-diiodophenyl)glutaramide; and the like.

3. 3-(3-methoxyphenyl)glutaramide

A sample of 18.7 g of 3-(3-methoxyphenyl)glutaronitrile preparedaccording to Preparation A, Part 3, is dissolved in 250 ml of acetone.This solution is stirred in an ice-bath and added are 125 ml of water,40 ml of 30% hydrogen peroxide and 25 ml of 10% sodium carbonate. Themixture is allowed to stand at room temperature over night and is thenconcentrated to a volume of about 125 ml. The residue is cooled and theresulting crystalline precipitate is collected, washed with water anddried under vacuum to give 17.4 g of 3-(3-methoxyphenyl)glutaramide, mp161°-162°.

4. Similarly, by following in principle the procedure of Part 3 of thispreparation, but substituting other suitable 3-phenylglutaramidesprepared according to the process of Preparation A, Part 4, othercorresponding 3-(substituted phenyl)glutaramides are prepared such as

3-(2-methoxyphenyl)glutaramide;

3-(4-methoxyphenyl)glutaramide;

3-(2-ethoxyphenyl)glutaramide;

3-(3-ethoxyphenyl)glutaramide;

3-(4-ethoxyphenyl)glutaramide;

3-(2-propoxyphenyl)glutaramide;

3-(3-propoxyphenyl)glutaramide;

3-(4-propoxyphenyl)glutaramide;

3-(4-butoxyphenyl)glutaramide;

3-(2-benzoyloxyphenyl)glutaramide;

3-(3-benzyloxyphenyl)glutaramide;

3-(4-benzyloxyphenyl)glutaramide, m.p. 205°-207° C.;

3-(4-methylphenyl)glutaramide, bp 194°-196° C.;

3-(2-methylphenyl)glutaramide;

3-(3-methylphenyl)glutaramide;

3-(3-ethylphenyl)glutaramide;

3-(4-ethylphenyl)glutaramide;

3-(2-ethylphenyl)glutaramide;

3-(2-isopropylphenyl)glutaramide;

3-(3-isopropylphenyl)glutaronitrole;

3-(4-isopropylphenyl)glutaramide, bp 192°-193° C.;

3-(2-trifluoromethylphenyl)glutaramide;

3-(3-trifluoromethylphenyl)glutaramide;

3-(4-trifluoromethylphenyl)glutaramide;

3-(2-methylthiophenyl)glutaramide;

3-(4-methylthiophenyl)glutaramide;

3-(2-ethylthiophenyl)glutaramide;

3-(4-ethylthiophenyl)glutaramide;

3-(2-butylthiophenyl)glutaramide;

3-(3-butylthiophenyl)glutaramide;

3-(4-methsulfinylphenyl)glutaramide;

3-(4-ethylsulfonylphenyl)glutaramide;

3-(2,4-dimethoxyphenyl)glutaramide;

3-(2,6-diethoxyphenyl)glutaramide;

3-(3,4-dibenzyloxyphenyl)glutaramide;

3-(3,5-diethylthiophenyl)glutaramide;

3-(2,6-dimethylsulfinylphenyl)glutaramide;

3-(2,6-dimethylsulfonylphenyl)glutaramide; and the like.

PREPARATION C: 2-Phenyl-1,3-propanediamine (Reaction Sequence 1)

1. 2-(3-methoxyphenyl)-1,3-propanediamine

A sodium hypobromite solution is prepared from 27 g of sodium hydroxideand 23 g of bromine in 200 ml of water at -3°. 15.2 G of3-(3-methoxyphenyl)glutaramide (prepared according to Preparation B,Part 1) are added in five equal portions to the sodium hypobromitesolution. The mixture is stirred at 0° C. until there is a clearsolution and is then stirred at room temperature for 1 hour and finallyat 70° for 30 minutes. It is cooled and extracted with twelve 70 mlportions of methylene chloride and with two 70 ml portions of toluene.The combined extracts are dried over sodium sulfate, concentrated anddistilled to yield 5.1 g of 2-(3-methoxyphenyl)-1,3-propanediamine, bp140° C. at 1 mm.

A small amount of the dihydrochloride salt is prepared by dissolving afew drops of the diamine in ethanol hydrogen chloride and adding etherto the resulting solution to crystallize the dihydrochloride of2-(3-methoxyphenyl)-1,3-propanediamine, mp 232°-234°.

2. Similarly, by following in principle the procedure of Part 1 of thispreparation but substituting other suitable 2-phenylglutaramidesprepared according to Preparation B, Parts 2, 3, or 4 for3-(3methoxyphenyl)glutaramide, other 2-phenyl-1,3-propanediamines areprepared, such as

2-phenyl-1,3-propanediamine, bp 85°-87° C./2 mm (as dihydrochloride[diHCl] salt, mp 258°-262° C.);

2-(2-chlorophenyl)1,3-propanediamine, bp 87°-92° C./0.05 mm (di HClsalt, mp 253°-257° C.);

2-(3-chlorophenyl)-1,3-propanediamine;

2-(4-chlorophenyl)-1,3-propanediamine;

2-(2-fluorophenyl)-1,3-propanediamine;

2-(3-fluorophenyl)-1,3-propanediamine;

2-(4-fluorophenyl)-1,3-propanediamine, (diHCl salt mp 292.5°-295° C.);

2-(2-bromophenyl)-1,3-propanediamine;

2-(3-bromophenyl)-1,3-propanediamine, bp 120°-125° C./0.02 mm (diHClsalt, mp 260°-265° C.);

2-(4-bromophenyl)-1,3-propanediamine;

2-(2-iodophenyl)-1,3-propanediamine;

2-(3-iodophenyl)-1,3-propanediamine;

2-(4-iodophenyl)-1,3-propanediamine;

2-(2,3-dichlorophenyl)-1,3-propanediamine;

2-(2,4-dichlorophenyl)-1,3-propanediamine, bp 110° C./0.01 mm (diHClsalt, mp 268°-270° C.);

2-(3,4-dichlorophenyl)-1,3-propanediamine;

2-(3,5-dichlorophenyl)-1,3-propanediamine;

2-(2,5-dichlorophenyl)-1,3-propanediamine;

2-(2,6-dichlorophenyl)-1,3-propanediamine, bp 126°-128° C./0.5 mm(dipicrate salt, mp 253°-255° C.);

2-(2,3-difluorophenyl)-1,3-propanediamine;

2-(2,4-difluorophenyl)-1,3-propanediamine;

2-(3,4-difluorophenyl)-1,3-propanediamine;

2-(2,5-difluorophenyl)-1,3-propanediamine;

2-(2,6-difluorophenyl)-1,3-propanediamine;

2-(3,5-difluorophenyl)-1,3-propanediamine;

2-(3,6-dibromophenyl)-1,3-propanediamine;

2-(2,4-dibromophenyl)-1,3-propanediamine;

2-(3,5-dibromophenyl)-1,3-propanediamine;

2-(2,4-diiodophenyl)-1,3-propanediamine;

2-(2,6-diiodophenyl)-1,3-propanediamine;

2-(2-methoxyphenyl)-1,3-propanediamine;

2-(3-methoxyphenyl)-1,3-propanediamine;

2-(4-methoxyphenyl)-1,3-propanediamine;

2-(2-ethoxyphenyl)-1,3-propanediamine;

2-(3-ethoxyphenyl)-1,3-propanediamine;

2-(4-ethoxyphenyl)-1,3-propanediamine;

2-(2-propoxyphenyl)-1,3-propanediamine;

2-(3-propoxyphenyl)-1,3-propanediamine;

2-(4-propoxyphenyl)-1,3-propanediamine;

2-(4-butoxyphenyl)-1,3-propanediamine;

2-(2-benzyloxyphenyl)-1,3-propanediamine;

2-(3-benzyloxyphenyl)-1,3-propanediamine;

2-(4-benzyloxyphenyl)-1,3-propanediamine;

2-(2-methylphenyl)-1,3-propanediamine;

2-(3-methylphenyl)-1,3-propanediamine;

2-(4-methylphenyl)-1,3-propanediamine;

2-(2-ethylphenyl)-1,3-propanediamine;

2-(3-ethylphenyl)-1,3-propanediamine;

2-(4-ethylphenyl)-1,3-propanediamine;

2-(2-isopropylphenyl)-1,3-propanediamine;

2-(3-isopropylphenyl)-1,3-propanediamine;

2-(4-isopropylphenyl)-1,3-propanediamine, bp 103°-108° C./0.01 mm (diHClsalt, mp 284°-287° C.);

2-(2-trifluoromethylphenyl)-1,3-propanediamine;

2-(3-trifluoromethylphenyl)-1,3-propanediamine;

2-(4-trifluoromethylphenyl)-1,3-propanediamine;

2-(2-methylthiophenyl)-1,3-propanediamine;

2-(4-methylthiophenyl)-1,3-propanediamine;

2-(2-ethylthiophenyl)-1,3-propanediamine;

2-(4-ethylthiophenyl)-1,3-propanediamine;

2-(2-butylthiophenyl)-1,3-propanediamine;

2-(3-butylthiophenyl)-1,3-propanediamine;

2-(4-methsulfinylphenyl)-1,3-propanediamine;

2-(4-ethylsulfonylphenyl)-1,3-propanediamine;

2-(2,4-dimethoxyphenyl)-1,3-propanediamine;

2-(2,6-diethoxyphenyl)-1,3-propanediamine;

2-(3,4-dibenzyloxyphenyl)-1,3-propanediamine;

2-(3,5-diethylthiophenyl)-1,3-propanediamine;

2-(2,6-dimethylsulfinylphenyl)-1,3-propanediamine;

2-(2,6-dimethylsulfonylphenyl)-1,3-propanediamine; and the like.

PREPARATION D: N-Methyl-2-phenyl-1,3-propane diamines (Reaction Sequence2)

1. Four and four-tenths (4.4) g of the ethyleneglycol acetal ofatropaldehyde is hydrolysed by reaction with 40 ml of water and 250 mgof oxalic acid in 200 ml of ethanol at 70° for about 1 hour. One andfour-tenths (1.4) g of N-methylhydrazine is added and the resultingmixture is allowed to stand for 4 hours at room temperature. The mixtureis then concentrated to about 50 ml, aqueous sodium bicarbonate is addedand the mixture is extracted with methylenechloride. The extract isconcentrated and distilled, to give 2.2 g of4,5-dihydro-1-methyl-4-phenyl-[1H]-pyrrazole, bp 66°-72°/0.03 mm; ms 160(M+).

A mixture of 3.8 g of 4,5-dihydro-1-methyl-4-phenyl-[1H]-pyrrazole, 50ml of glacial acetic acid, 10 ml of 10% hydrochloric acid and 1 g of acatalyst consisting of 5% platinum on charcoal is stirred under ahydrogen atmosphere for about 6 hours until the calculated amount ofhydrogen has been consumed. The mixture is filtered and the filtrate isconcentrated under vacuum. The residue is treated with isopropanol andtoluene and is concentrated again to remove as much of the water aspossible. The residue is refluxed with ether for 3 hours until a powderysolid forms which is collected by filtration. Recrystallization fromethanol gives N-methyl-2-phenyl-1,3-propanediamine hydrochloride, mp264°-267° C.

2. In a similar manner by substituting other ethylene glycol acetals ofappropriately phenyl-ring substituted atropaldehydes, otherN-methyl-2-substituted phenyl-1,3-propanediamines are prepared such as

N-methyl-2-(2-fluorophenyl)-1,3-propanediamine;

N-methyl-2-(3-fluorophenyl)-1,3-propanediamine;

N-methyl-2-(4-fluorophenyl)-1,3-propanediamine;

N-methyl-2-(2-chlorophenyl)-1,3-propanediamine;

N-methyl-2-(3-chlorophenyl)-1,3-propanediamine;

N-methyl-2-(4-chlorophenyl)-1,3-propanediamine;

N-methyl-2-(2-bromophenyl)-1,3-propanediamine;

N-methyl-2-(3-bromophenyl)-1,3-propanediamine;

N-methyl-2-(4-bromophenyl)-1,3-propanediamine;

N-methyl-2-(2-iodophenyl)-1,3-propanediamine;

N-methyl-2-(3-iodophenyl)-1,3-propanediamine;

N-methyl-2-(4-iodophenyl)-1,3-propanediamine;

N-methyl-2-(2,4-dichlorophenyl)-1,3-propanediamine;

N-methyl-2-(3,4-dichlorophenyl)-1,3-propanediamine;

N-methyl-2-(3,5-dichlorophenyl)-1,3-propanediamine;

N-methyl-2-(2,5-dichlorophenyl)-1,3-propanediamine;

N-methyl-2-(2,6-dichlorophenyl)-1,3-propanediamine;

N-methyl-2-(2,3-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(2,4-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(3,4-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(2,5-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(2,6-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(3,5-difluorophenyl)-1,3-propanediamine;

N-methyl-2-(3,6-dibromophenyl)-1,3-propanediamine;

N-methyl-2-(2,4-dibromophenyl)-1,3-propanediamine;

N-methyl-2-(3,5-dibromophenyl)-1,3-propanediamine;

N-methyl-2-(2,4-diiodophenyl)-1,3-propanediamine;

N-methyl-2-(2,6-diiodophenyl)-1,3-propanediamine;

N-methyl-2-(2-hydroxyphenyl)-1,3-propanediamine;

N-methyl-2-(2-methoxyphenyl)-1,3-propanediamine;

N-methyl-2-(3-methoxyphenyl)-1,3-propanediamine;

N-methyl-2-(4-methoxyphenyl)-1,3-propanediamine;

N-methyl-2-(2-ethoxyphenyl)-1,3-propanediamine;

N-methyl-2-(3-ethoxyphenyl)-1,3-propanediamine;

N-methyl-2-(4-ethoxyphenyl)-1,3-propanediamine;

N-methyl-2-(2-propoxyphenyl)-1,3-propanediamine;

N-methyl-2-(3-propoxyphenyl)-1,3-propanediamine;

N-methyl-2-(4-propoxyphenyl)-1,3-propanediamine;

N-methyl-2-(3-isopropoxyphenyl)-1,3-propanediamine;

N-methyl-2-(4-butoxyphenyl)-1,3-propanediamine;

N-methyl-2-(2-benzyloxyphenyl)-1,3-propanediamine;

N-methyl-2-(3-benzyloxyphenyl)-1,3-propanediamine;

N-methyl-2-(4-benzyloxyphenyl)-1,3-propanediamine;

N-methyl-2-(2-methylphenyl)-1,3-propanediamine;

N-methyl-2-(3-methylphenyl)-1,3-propanediamine;

N-methyl-2-(4-methylphenyl)-1,3-propanediamine;

N-methyl-2-(2ethylphenyl)-1,3-propanediamine;

N-methyl-2-(3-ethylphenyl)-1,3-propanediamine;

N-methyl-2-(4-ethylphenyl)-1,3-propanediamine;

N-methyl-2-(3-propylphenyl)-1,3-propanediamine;

N-methyl-2-(2-isopropylphenyl)-1,3-propanediamine;

N-methyl-2-(3-isopropylphenyl)-1,3-propanediamine;

N-methyl-2-(4-isopropylphenyl)-1,3-propanediamine;

N-methyl-2-(4-butylphenyl)-1,3-propanediamine;

N-methyl-2-(2-trifluoromethylphenyl)-1,3-propanediamine;

N-methyl-2-(3-trifluoromethylphenyl)-1,3-propanediamine;

N-methyl-2-(4-trifluoromethylphenyl)-1,3-propanediamine;

N-methyl-2-(2-methylthiophenyl)-1,3-propanediamine;

N-methyl-2-(4-methylthiophenyl)-1,3-propanediamine;

N-methyl-2-(2-ethylthiophenyl)-1,3-propanediamine;

N-methyl-2-(4-ethylthiophenyl)-1,3-propanediamine;

N-methyl-2-(2-butylthiophenyl)-1,3-propanediamine;

N-methyl-2-(3-butylthiophenyl)-1,3-propanediamine;

N-methyl-2-(4-methylsulfinylphenyl)-1,3-propanediamine;

N-methyl-2-(4-ethylsulfonylphenyl)-1,3-propanediamine;

N-methyl-2-(2,4-dimethoxyphenyl)-1,3-propanediamine;

N-methyl-2-(2,6-diethoxyphenyl)-1,3-propanediamine;

N-methyl-2-(3,4-dibenzyloxyphenyl)-1,3-propanediamine;

N-methyl-2-(3,5-diethylthiophenyl)-1,3-propanediamine;

N-methyl-2-(2,6-dimethylsulfinylphenyl)-1,3-propanediamine;

N-methyl-2-(2,6-dimethylsulfonylphenyl)-1,3-propanediamine; and thelike.

3. By following in principle the procedure of Parts A and B of thisPreparation but substituting other N-alkylhydrazines such asN-ethylhydrazine, N-propylhydrazine or N-butylhydrazine forN-methylhydrazine, other diamines are obtained such as

N-ethyl-2-phenyl-1,3-propanediamine;

N-propyl-2-phenyl-1,3-propanediamine;

N-butyl-2-phenyl-1,3-propanediamine; and the like.

PREPARATION E: 2-Phenylglutaramides (Reaction Sequence 3)

1. Twenty-five g of 4-fluorobenzylcyanide is mixed with approximately3.5 ml of freshly distilled acrylonitrile in a suitable reaction vessel.To this stirred mixture is added dropwise a solution of 80 mg of sodiummethoxide in 1 ml of methanol. When about half of the sodium methoxideis added, there is an exothermic reaction. After all the sodiummethoxide is added, the mixture is kept on a steam-bath for 2 hours andis then dissolved in toluene and washed with water. The toluene isremoved by evaporation and the residue is separated into its componentsby fractional distillation to give 18 g of 4-fluorobenzylcyanide, and 2g of 2-(4-fluorophenyl)glutaronitrile, bp 118°-122° C. at 0.03 mm.

A reaction mixture consisting of 3.5 g of2-(4-fluorophenyl/glutaronitrile, 25 ml of concentrated sulfuric acidand 1 ml of water is allowed to stand at room temperature over night.The solution is poured into 300 g of ice and is then neutralized withammonium hydroxide. The product is extracted out with chloroform in acontinuous extractor. After three days the product that has formed as acrystalline material in the chloroform is collected to yield 3.01 g of2-(4-fluorophenyl)glutaramide, m.p. 154°-157° C.

2. Similarly, by following in principle the procedure of Part 3 of thispreparation, but substituing other benzylcyanides for4-fluorobenzylcyanide, other 2-phenylglutaramides are prepared, such as

2-phenylglutaroamide;

2-(2-chlorophenyl)glutaramide;

2-(3-chlorophenyl)glutaramide;

2-(4-chlorophenyl)glutaramide;

2-(2-fluorophenyl)glutaramide;

2-(3-fluorophenyl)glutaramide;

2-(2-bromophenyl)glutaramide;

2-(3-bromophenyl)glutaramide;

2-(4-bromophenyl)glutaramide;

2-(2-iodophenyl)glutaramide;

2-(3-iodophenyl)glutaramide;

2-(4-iodophenyl)glutaramide;

2-(2,3-dichlorophenyl)glutaramide;

2-(2,4-dichlorophenyl)glutaramide;

2-(3,4-dichlorophenyl)glutaramide;

2-(3,5-dichlorophenyl)glutaramide;

2-(2,5-dichlorophenyl)glutaramide;

2-(2,3-difluorophenyl)glutaramide;

2-(2,4-difluorophenyl)glutaramide;

2-(3,4-difluorophenyl)glutaramide;

2-(2,5-difluorophenyl)glutaramide;

2-(2,6-difluorophenyl)glutaramide;

2-(3,5-difluorophenyl)glutaramide;

2-(2,6-dibromophenyl)glutaramide;

2-(2,4-dibromophenyl)glutaramide;

2-(3,5-dibromophenyl)glutaramide;

2-(2,4-diiodophenyl)glutaramide;

2-(2,6-diiodophenyl)glutaramide;

2-(3-methoxyphenyl)glutaramide;

2-(2-methoxyphenyl)glutaramide;

2-(4-methoxyphenyl)glutaramide;

2-(2-ethoxyphenyl)glutaramide;

2-(3-ethoxyphenyl)glutaramide;

2-(4-ethoxyphenyl)glutaramide;

2-(2-propoxyphenyl)glutaramide;

2-(3-propoxyphenyl)glutaramide;

2-(4-propoxyphenyl)glutaramide;

2-(4-butoxyphenyl)glutaramide;

2-(2-benzyloxyphenyl)glutaramide;

2-(3-benzyloxyphenyl)glutaramide;

2-(4-benzyloxyphenyl)glutaramide;

2-(2-methylphenyl)glutaramide;

2-(3-methylphenyl)glutaramide;

2-(4-methylphenyl)glutaramide;

2-(2-ethylphenyl)glutaramide;

2-(3-ethylphenyl)glutaramide;

2-(4-ethylphenyl)glutaramide;

2-(2-isopropylphenyl)glutaramide;

2-(3-isopropylphenyl)glutaronitrole;

2-(4-isopropylphenyl)glutaramide;

2-(2-trifluoromethylphenyl)glutaramide;

2-(3-trifluoromethylphenyl)glutaramide;

2-(4-trifluoromethylphenyl)glutaramide;

2-(2-methylthiophenyl)glutaramide;

2-(4-methylthiophenyl)glutaramide;

2-(2-ethylthiophenyl)glutaramide;

2-(4-ethylthiophenyl)glutaramide;

2-(2-butylthiophenyl)glutaramide;

2-(3-butylthiophenyl)glutaramide;

2-(4-methylsulfinylphenyl)glutaramide;

2-(4-ethylsulfonylphenyl)glutaramide;

2-(2,4-dimethoxyphenyl)glutaramide;

2-(2,6-diethoxyphenyl)glutaramide;

2-(3,5-diethylthiophenyl)glutaramide;

2-(2,6-dimethylsulfinylphenyl)glutaramide;

2-(2,6-dimethylsulfonylphenyl)glutaramide; and the like.

PREPARATION F: 1-phenyl-1,3-propanediamines (Reaction Sequence 3)

A. 1-Phenyl-1,3-propanediamine

A solution of 27 g of potassium hydroxide in 150 ml of water is cooledto -2° C. and 17 g of bromine is added in a thin stream. The mixture isstirred for 10 min. and 10 g of 2-phenylglutaramide is then added.Stirring is continued while the temperature is kept at -3° to +2° C.until there is a clear solution (about 15 min.). The solution is thenstirred at room temperature for 30 mins. and finally at 60° C. for 90min. It is cooled and extracted several times with methylene chlorideand the combined extracts are dried over sodium sulfate, filtered andconcentrated. The residue is distilled to yield 4.2 g of1-phenyl-1,3-propanediamine, b.p. 84°-87° C. at 0.5 mm.

When 2.2 g of the diamine is dissolved in 25 ml of ethanol that contains1.3 g of hydrogen chloride there is crystallization of thedihydrochloride salt which is collected and dried at 80° C. under vacuumto yield 2.8 g of 1-phenyl-1,3-propanediamine dihydrochloride, m.p.244°-246° C.

B. Other 1-phenylpropanediames are prepared by following in principlethe procedure of Part A of this procedure substituting other2-phenylglutaramides of Part 2 of Preparation E for 2-phenylgutaramidein Part A of this procedure.

PREPARATION G: β-Amino-2-cinnamonitriles (Reaction Sequence 4)

1. β-Amino-2-trifluoromethylcinnamonitrile

A mixture consisting of 9.3 g of 2-trifluoromethylbenzonitrile, 4.5 g ofacetonitrile, 4.3 g of sodium amide and 100 ml of ether is stirred andrefluxed under nitrogen over night. The resulting solid is collected ona Buchner-funnel, washed with ether and dissolved in approximately 100ml of cold ethanol. Crushed ice is added to this solution until thetotal volume is about 700 ml. This mixture is allowed to stand forseveral hours. The resulting solid precipitate is collected byfiltration then dissolved in methanol and decolorizing charcoal isadded. The charcoal/methanol mixture is filtered and the filtrate isgradually treated with water until crystallization is judged complete.The crystalline solid is collected and dried under vacuum, to give 7.75g of β-amino-2-trifluoromethylcinnamonitrile, mp 101°-103°.

2. Similarly, by following in principle the procedure of Part 1 of thisPreparation, but substituting other appropriately substitutedbenzonitriles for 2-trifluoromethylbenzonitrile, other correspondingβ-amino-substituted cinnamonitriles are prepared such as

β-aminocinnamonitrile;

β-amino-2-fluorocinnamonitrile;

β-amino-3-fluorocinnamonitrile;

β-amino-4-fluorocinnamonitrile;

β-amino-2-chlorocinnamonitrile;

β-amino-3-chlorocinnamonitrile;

β-amino-4-chlorocinnamonitrile;

β-amino-3-bromocinnamonitrile;

β-amino-4-iodocinnamonitrile;

β-amino-2-methylcinnamonitrile;

β-amino-4-methylcinnamonitrile, mp 111°-113° C.;

β-amino-2-ethylcinnamonitrile;

β-amino-4-t-butylcinnamonitrile;

β-amino-2-methoxycinnamonitrile, mp 74°-75° C.;

β-amino-3-ethoxycinnamonitrile;

β-amino-4-isopropoxycinnamonitrile;

β-amino-2-methylthiocinnamonitrile;

β-amino-4-isobutylthiocinnamonitrile;

β-amino-4-methylsulfinylcinnamonitrile;

β-amino-4-methylsulfonylcinnamonitrile;

β-amino-2,4-difluorocinnamonitrile;

β-amino-2,6-dichlorocinnamonitrile;

β-amino-2,6-dibromocinnamonitrile;

β-amino-2,4-diiodocinnamonitrile;

β-amino-2,4-dimethylcinnamonitrile;

β-amino-2,6-disopropylcinnamonitrile;

β-amino-2,4-dimethoxycinnamonitrile;

β-amino-2,6-diethoxycinnamonitrile;

β-amino-2,4-dimethylthiocinnamonitrile;

β-amino-2,6-dimethylsulfinylcinnamonitrile; and the like.

PREPARATION H: 1-phenyl-1,3-propanediamines (Reaction Sequence 4)

1. 1-(2-Trifluoromethylphenyl)-1,3-propanediamine

Sixty (60) ml of 1 molar borane in tetrahydrofuran is added to asolution of 7.6 g of β-amino-2-trifluoromethylcinnamonitrile (preparedaccording to Preparation D, Part 1) in 100 ml of ether. The mixture isstirred at room temperature overnight, then treated with 10 ml of water,and stirred for 45 minutes. The resulting mixture is concentrated underreduced pressure and 200 ml of isopropanol and 80 ml of 20% hydrochloricacid are added thereto. This mixture is refluxed for 2 hours, thenconcentrated to a small volume. The residue is made alkaline by additionof excess of 20% sodium hydroxide and is extracted 3 times withmethylene chloride. The extracts are combined, concentrated anddistilled to give 1.7 g of1-(2-trifluoromethylphenyl)-1,3-propanediamine, bp 73°-77° C./0.1 mm.

The hydrochloric salt is obtained by dissolving the diamine in ethanolichydrogen chloride and adding ether to this solution to give the diHClsalt of 1-(2-trifluoromethylphenyl)-1,3-propanediamine, mp 213°-127°.

2. Similarly, by following in principle the process of Part 1 of thispreparation but substituting a suitable β-aminocinnamonitrile (preparedaccording to Preparation D, Part 2) forβ-amino-2-trifluoromethylcinnamonitrile, other correspondingpropanediamines are prepared such as

1-phenyl-1,3-propanediamine, bp 84°-87° C./0.5 mm (diHCl salt, mp244°-246° C.);

1-(2-fluorophenyl)-1,3-propanediamine;

1-(3-fluorophenyl)-1,3-propanediamine;

1-(4-fluorophenyl)-1,3-propanediamine, bp 84°-88° C./0.7 mm (diHCl salt262°-266° C.);

1-(2-chlorophenyl)-1,2-propanediamine;

1-(3-chlorophenyl)-1,2-propanediamine;

1-(4-chlorophenyl)-1,2-propanediamine;

1-(3-bromophenyl)-1,2-propanediamine;

1-(4-iodophenyl)-1,2-propanediamine;

1-(2-methylphenyl)-1,2-propanediamine;

1-(4-methylphenyl)-1,2-propanediamine;

1-(2-ethylphenyl)-1,2-propanediamine;

1-(4-t-butylphenyl)-1,2-propanediamine;

1-(2-methoxyphenyl)-1,2-propanediamine;

1-(3-methoxyphenyl)-1,2-propanediamine, b.p. 120°-126° C. at 1 mm (diHClsalt, m.p. 225°-227° C.);

1-(3-ethoxyphenyl)-1,2-propanediamine;

1-(4-isopropoxyphenyl)-1,2-propanediamine;

1-(2-methylthiophenyl)-1,2-propanediamine;

1-(4-isobutylthiophenyl)-1,2-propanediamine;

1-(4-methylsulfinylphenyl)-1,2-propanediamine;

1-(4-methylsulfonylphenyl)-1,2-propanediamine;

1-(2,4-difluorophenyl)-1,2-propanediamine;

1-(2,6-dichlorophenyl)-1,2-propanediamine;

1-(2,6-dibromophenyl)-1,2-propanediamine;

1-(2,4-diiodophenyl)-1,2-propanediamine;

1-(2,4-dimethylphenyl)-1,2-propanediamine;

1-(2,6-disopropylphenyl)-1,2-propanediamine;

1-(2,4-dimethoxyphenyl)-1,2-propanediamine;

1-(2,6-diethoxyphenyl)-1,2-propanediamine;

1-(2,4-dimethylthiophenyl)-1,2-propanediamine;

1-(2,6-dimethylsulfinyl; and the like.

EXAMPLE 1: 2-Amino-5-phenyl-1,4,5,6-tetrahydropyrimidines.

A. A solution of 1.55 g of 2-(3-bromophenyl)-1,3-propanediamine(prepared in accordance with Preparation C, Part 2) and 0.72 g ofcyanogenbromide in 300 ml of methanol is maintained at room temperaturefor three days and is then refluxed for 6 hours. The solvent isevaporated off by a rotary evaporator. The residue is dissolved inboiling isopropanol which then is filtered through a steam-jacketedfunnel. The crystals which form as the filtrate are cooled is collectedby filtration and dried under vacuum to give 0.87 g of the hydrobromidesalt of 2-amino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine, mp223°-227° C.

B. A stirred mixture consisting of 3.25 g of 2-phenyl-1,3-propanediamine(prepared in accordance with Preparation C) and 3.02 g of2-methyl-2-thiopseudourea sulfate ([CH₃ SC(NH)NH₂ ]₂.H₂ SO₄) in a smallflask is immersed in a 245° C. oil bath. The temperature is raised to265° C. when the reaction mixture solidifies. When the reaction mixturemelts again, it is stirred for about five minutes then is removed fromthe oil-bath. The contents are refluxed with 50 ml of methanol until apowder is formed. The mixture is cooled and the solid product iscollected on a Buchner-funnel, washed with 30% ether in methanol and isair-dried to give 3.7 g of crude product. Recrystallization from 20 mlof water yields 2.25 g of 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidinesulfate, mp 264°-267° C.

C. By following in principle the procedures of Parts A or B of thisexample but substituting other appropriate 2-(substitutedphenyl)-1,3-propanediamines prepared according to Preparation C for2-(3-bromophenyl)-1,3-propanediamine and 2-phenyl-1,3-propanediamineother compounds of this invention are prepared such as

2-amino-5-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,3-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3,6-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,4-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine

2-amino-5-(3-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-methsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(4-ethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-diethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(3,5-diethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-5-(2,6-dimethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine; andthe like.

EXAMPLE 2: 1-Alkyl 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidines.

A. 1-methyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine

A slurry of 0.55 g of the dihydrochloride salt ofN-methyl-2-phenyl-1,3-propanediamine in 25 ml of ethanol is stirred with0.3 g of sodium methoxide for 30 min. The precipitated sodium chlorideis removed by filtration and the filtrate is concentrated. The residueis mixed with 0.322 g of 2-methyl-2-thiopseudourea sulfate and themixture is stirred in a 240° C. oil-bath for 10 min. The crude reactionproduct is then refluxed with isopropanol for 2 hours, cooled and thesolid is collected and recrystallized from 6-7 ml of water to give 0.2 gof the sulfate salt of1-methyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine, m.p. 254°-257°C.

B. In a similar manner, by following in principle the procedure of PartA of this example but substituting otherN-methyl-2-phenyl-1,3-propanediamines prepared in accordance withPreparation D, Part 2 for N-methyl-2-phenyl-1,3-propanediamine othercompounds of this invention are prepared such as

1-methyl-5-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-amino-5-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,3-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-amino-5-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,6-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3,6-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,4-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,6-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-amino-5-(2-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-amino-5-(4-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-methsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(4-ethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,6-diethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(3,5-diethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-5-(2,6-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-amino-5-(2,6-dimethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;and the like.

C. In a similar manner, by following in principle the procedure of PartA of this example but substituting otherN-alkyl-2-phenyl-1,3-propanediamines prepared in accordance withPreparation D, Part 3 for N-methyl-2-phenyl-1,3-propanediamine othercompounds of this invention are prepared such as

1-ethyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine;

1-propyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine;

1-butyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine; and other N-alkylhomologs of the compounds of Part B of this Example.

EXAMPLE 3: 2-Alkylcarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidines

A. Acetamido-5-phenyl-1,4,5,6-tetrahydropyrimidine

A slurry of 600 mg (2.67 mmole) of the sulfate salt of2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine (prepared in accordancewith Example 1) in 50 ml of ethanol and 145 mg (2.67 mmole) of sodiummethoxide are stirred for 2 hours. The mixture is filtered to remove theinsoluble sodium chloride and the solvent is removed under vacuum. Theoil residue is dissolved in 100 ml of methylene chloride, 415 mg (1.33mmole) of N,N',N",N"'-tetraacetylglycoluril is added and the resultingsolutions is stirred at room temperature overnight. A precipitate thathas formed is removed by filtration and the filtrate is concentrated.The residue is treated with approximately 25 ml of anacetonitrile-ethyl=acetate mixture and the insoluble product iscollected by filtration to yield 320 mg of a product having a m.p.241°-245° C. Upon purification by recrystallization from methanol,2-acetamido-5-phenyl-1,4,5,6-tetrahydropyrimidine is obtained, m.p.246°-249° C.

B. Similarly, by following the procedure of Part A of this example butsubstituting tetrapropionylglycoluril or tetrabutyrylglycoluril fortetracetylglycoluril other amides of this invention are prepared such as

2-propionamido-5-phenyl-1,4,5,6-tetrahydropyrimidine or

2-butyramido-5-phenyl-1,4,5,6-tetrahydropyrimidine.

C. Similarly, by following the procedures of Parts A and B of thisexample, but substituting the other2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine of Example 1, Part C. for2-amino-5-phenyl-1,4,5,6-tetrahydropyrimide, the corresponding2-acetamido, 2-propionamido or2-butyramido-5-phenyl-1,4,5,6-tetrahydropyrimidines are prepared.

EXAMPLE 4: 1-Alkyl2-alkylcarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidines

A. By following in principle the procedure of Example 3, Parts A and Bbut substituting 1-methyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidinefor 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine other compounds ofthis invention are prepared such as

1-methyl-2-acetamido-5-phenyl-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-propionamido-5-phenyl-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-butyramido-5-phenyl-1,4,5,6-tetrahydropyrimidine; and thelike.

B. Similarly, by following the procedures of Part A of this example, butsubstituting the other1-alkyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine of Example 2, PartC for 1-methyl-2-amino-5-phenyl-1,4,5,6-tetrahydropyrimide, thecorresponding 1-alkyl-2-acetamido, 2-propionamido or2-butyramido-5-phenyl-1,4,5,6-tetrahydropyrimidines are prepared whichcorrespond to the 2-amines of Example 2, Part C.

EXAMPLE 5: 2-Alkoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidines

A.2-Methoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine

A solution of 2.61 g (14.5 m. mole) of2-(3-methoxyphenyl)-1,3-propanediamine in 200 ml of methanol is combinedwith a solution of 3.0 g (14.55 m. mole) of1,3-bis(methoxycarbonyl)-S-methylisothiourea in 200 ml of methanol andallowed to stand at room temperature over night. The crystalline productwhich separates is collected, washed with methanol and dried at 78°under vacuum to give 2.62 g of2-methoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine,mp 218°-221°.

B. Similarly, by following in principle the process of Part A of thisexample but substituting other 2-(optionally substitutedphenyl)-1,3-propanediamines prepared according to the process ofPreparation C, Part 2 for 2-(3-methoxyphenyl)-1,3-propanediamine), othercompounds of this invention are prepared such as

2-methoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine, m.p.333°-336° C.;

2-methoxycarbonylamino-5-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine,mp 353°-357° C.;

2-methoxycarbonylamino-5-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine,mp 225°-235° C. (decomposes) mp HCl salt 179°-182° C.;

2-methoxycarbonylamino-5-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine,mp 213°-215° C.;

2-methoxycarbonylamino-5-(4-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine,(HCl salt, mp 209°-210° C.);

2-methoxycarbonylamino-5-(3,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine,m.p. 231°-234° C.;

2-methoxycarbonylamino-5-(2,3-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,6-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3,6-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,4-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,6-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine,ms 275 (M+);

2-methoxycarbonylamino-5-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(3-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(4-ethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-5-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-(2,6-diethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-(3,5-diethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-(2,6-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-(2,6-dimethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;and the like.

C. Similarly, by following in principle the procedures of Part A of thisexample but substituting otherbis-1,3(alkoxycarbonyl)-S-methylisothiourea ormono-1-alkoxycarbonyl-S-methylisothiourea such as1-ethoxycarbonyl-S-methylisothiourea or1-butoxycarbonyl-S-1-propoxycarbonyl-S-methylisothiourea forbis-1,3-(methoxycarbonyl)-S-methylisothiourea and a suitable2-phenyl-1,3-propanediamine for 2-(methoxyphenyl)-1,3-propanediamine,other 2-alkoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidines areprepared such as

2-ethoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine, mp338°-343° C.;

2-isopropoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine, mp335°-342° C.; ms 261 (M+);

2-n-butoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine;

2-n-propoxycarbonylamino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine,mp 205°-206° C.;

2-i-propoxycarbonylamino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine,mp 199°-201° C.; and the like.

EXAMPLE 6:1-Alkyl-2-alkoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidines

A. 1-Methyl-2-methoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine

To a solution of 1.5 g of the dihydrochloride ofN-methyl-2-phenyl-1,3-propane diamine (prepared in accordance withPreparation F, Part A) in 200 ml of methanol is added first 0.68 g ofsodium methoxide in a little methanol and then a solution of 1.3 g of1,3-bis(methoxycarbonyl)-S-methylisothiourea in 200 ml of methanol. Thismixture is allowed to stand at room temperature of 16 hours, is refluxedfor 1 hour and is then concentrated to near dryness. The residue isdissolved in 50 ml of 3% hydrochloric acid and the resulting solution iswashed with ether to remove non-basis impurities. The product is thenprecipitated by addition of saturated sodium bicarbonate. The solid iscollected, washed with fresh water and dried under vacuum to give 0.99 gof product, mp 177-179. Recrystallization from ether gives1-methyl-2-methyoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine,mp 176°-177°.

B. In a similar manner by substituting otherN-methyl-2-phenyl-1,3-propanediamines (prepared in accordance withPreparation F, Part B) for N-methyl-2-phenyl-1,3-propanediamine, othercompounds of this invention are prepared such as

1-methyl-2-alkoxycarbonylamino-5-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-hydroxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-isopropoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-benzyloxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-t-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-propylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-butylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-methylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(4-ethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,6-dihydroxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(3,5-dibutoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,6-dimethylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-dibutylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,6-dimethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

1-methyl-2-alkoxycarbonylamino-5-(2,4-diethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;and the like.

EXAMPLE 7: 2-Amino-4-phenyl-1,4,5,6-tetrahydropyrimidines

A. A solution of 1.32 g of the dihydrochloride salt of1-phenyl-1,3-propanediamine in a little water is made alkaline withexcess of 30% sodium hydroxide and the free diamine is extracted 3 timeswith toluene. The extracts are combined, the toluene is evaporated andthe residue is dissolved in 250 ml of methanol. A solution of 0.64 g ofcyanogen bromide in methanol is added and the mixture is allowed tostand at room temperature for 5 hours and is then refluxed for 1 hour.The solvent is removed under vacuum to give an oil residue which isdissolved in 25 ml of isopropanol and the product crystallizes out togive 0.59 g of fine needles of2-amino-4-phenyl-1,4,5,6-tetrahydropyrimidine, mp 192°-194°,hydrobromide.

B. In a similar manner, by substituting the appropriate 1-(substitutedphenyl)-1,3-propanediamine prepared in accordance with Preparation E forphenyl-1,3-propanediamine, other compounds of this invention areprepared such as

2-amino-4-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,3-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3,6-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,4-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine (hydrobromidesalt), m.p. 189°-191° C.;

2-amino-4-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-methsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(4-ethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-diethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(3,5-diethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-amino-4-(2,6-dimethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine; andthe like.

EXAMPLE 8: 2-Alkylcarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidines

A. By following in principle the procedure of Example 3, Part A butsubstituting 2-amino-4-phenyl-1,4,5,6-tetrahydropyrimidine for2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine, the corresponding2-acetamido-4-phenyl-1,4,5,6-tetrahydropyrimidine is obtained.

B. Similarly, by following the procedure of Part A of this example butsubstituting tetrapropionylglycoluril or tetrabutyrylglycoluril fortetracetylglycoluril other amides of this invention are prepared such as

2-propionamido-4-phenyl-1,4,5,6-tetrahydropyrimidine or

2-butyramido-4-phenyl-1,4,5,6-tetrahydropyrimidine.

C. Similarly, by following the procedures of Parts A and B of thisexample, but substituting the other2-amino-4-phenyl-1,4,5,6-tetrahydropyrimidine of Example 7, Part C for2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine, the corresponding2-acetamido, 2-propionamido or2-butyramido-4-phenyl-1,4,5,6-tetrahydropyrimidines are prepared.

EXAMPLE 9: 2-Alkoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidines

A.2-Methoxycarbonylamino-4-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine

A solution of 0.93 g of 1-(4-fluorophenyl)1,3-propanediamine and 1.2 gof 1,3-bis(methoxycarbonyl)-S-methylisothiourea in 300 ml of methanol isrefluxed for 2 hours and then concentrated to 25 ml to give crystalls of1.02 g of product having a m.p. 209°-214° C. Recrystallization of thisproduct from 75 ml of methanol yields 0.8 g of2-methoxycarbonylamino-4-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine,m.p. 211°-212° C.

The hydrochloride salt is prepared from ethanol containing hydrogenchloride, m.p. 166°-168° C.

B. Similarly, by following in principle the process of Part A of thisexample but substituting other 1-(optionally substitutedphenyl)-1,3-propanediamines prepared according to the process ofPreparation G, Part 2 for 1-(3-methoxyphenyl)-1,3-propanediamine, othercompounds of this invention are prepared such as

2-methoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine, m.p.186°-190° C.;

2-methoxycarbonylamino-4-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-chlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-fluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-iodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,5-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,3-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,4-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;2-methoxycarbonylamino-4-(3,5-difluorophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3,6-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,4-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3,5-dibromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,4-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-diiodophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-ethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-propoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-butoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-methylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine,m.p. 198°-200° C.;

2-methoxycarbonylamino-4-(2-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-ethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine,m.p. 195°-197° C.;

2-methoxycarbonylamino-4-(3-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-methylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-ethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3-butylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-methsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(4-ethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-diethoxyphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(3,5-diethylthiophenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-dimethylsulfinylphenyl)-1,4,5,6-tetrahydropyrimidine;

2-methoxycarbonylamino-4-(2,6-dimethylsulfonylphenyl)-1,4,5,6-tetrahydropyrimidine;and the like.

C. Similarly, by following in principle the procedures of Part A of thisexample but substituting otherbis-1,3(alkoxycarbonyl)-S-methylisothiourea ormono-1-alkoxycarbonyl-S-methylisothiourea such as1-ethoxycarbonyl-S-methylisothiourea,1-propoxycarbonyl-S-methylisothiourea or1-butoxycarbonyl-S-methylisothiourea forbis-1,3-(methoxycarbonyl)-S-methylisothiourea and a suitable1-phenyl-1,3-propanediamine for 1-(4-fluorophenyl)-1,3-propanediamine,other 2-alkoxycarbonylamino4-phenyl-1,4,5,6-tetrahydropyrimidines areprepared such as

2-ethoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine;

2-isopropoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine;

2-n-propoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine, m.p.134°-137° C.;

2-n-butoxycarbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine;

2-n-propoxycarbonylamino-4-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine;

2-i-propoxycarbonylamino-4-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine;and the like.

The subject matter claimed is:
 1. A compound selected from the group ofcompounds represented by the formula ##STR13## wherein A is H or##STR14## where R is alkyl of one through six carbon atoms; X ishydrogen, fluoro, chloro, bromo, iodo, hydroxy, alkoxy of one throughfour carbon atoms, benzyloxy, alkyl of one through four carbon atoms,alkylthio of one through four carbon atoms, alkylsulfinyl of one throughfour carbon atoms, alkylsulfonyl of one through four carbon atoms ortrifluoromethyl; andY is hydrogen or is the same as X; and R¹ ishydrogen or alkyl of one through four carbon atoms; the phenylsubstituent carrying the X and Y is at the 4- or 5-position of thetetrahydropyrimidine ring when R¹ is hydrogen or is at the 5-positionwhen R¹ is alkyl; and the pharmaceutically acceptable salts thereof. 2.The compound of claim 1 where A is H and the moiety represented by theformula ##STR15## is at the 5-position of the1,4,5,6-tetrahydropyrimidine ring.
 3. The compound of claim 2 wherein R¹is hydrogen.
 4. The compound of claim 3 wherein X and Y are eachhydrogen, namely 2-amino-5-phenyl-1,4,5,6-tetrahydropyrimidine.
 5. Thecompound of claim 3 wherein X and Y are each chloro.
 6. The compound ofclaim 5 wherein X and Y are at the 3,4-positions, namely2-amino-5-(3,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.
 7. Thecompound of claim 5 wherein X and Y are at the 2,4-positions, namely2-amino-5-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.
 8. Thecompound of claim 5 wherein X and Y are at the 2,6-positions, namely2-amino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.
 9. Thecompound of claim 3 wherein X is hydrogen and Y is fluoro.
 10. Thecompound of claim 9 wherein Y is 4-fluoro, namely2-amino-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine.
 11. Thecompound of claim 3 wherein X is hydrogen and Y is 3-bromo, namely2-amino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine.
 12. The compoundof claim 3 wherein X is hydrogen and Y is 3-chloro, namely2-amino-5-(3-chlorophenyl)-1,4,5,6-tetrahydropyrimidine.
 13. Thecompound of claim 3 wherein X is hydrogen and Y is 3-methoxy, namely2-amino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine.
 14. Thecompound of claim 1 where A is hydrogen, the moiety represented by theformula ##STR16## is at the 4-position of the1,4,5,6-tetrahydropyrimidine ring and R¹ is hydrogen.
 15. The compoundof claim 14 wherein X and Y are both hydrogen, namely2-amino-4-phenyl-1,4,5,6-tetrahydropyrimidine.
 16. The compound of claim14 wherein X and Y are both chloro.
 17. The compound of claim 14 whereinX is hydrogen and Y is 2-trifluoromethyl, namely2-amino-4-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine. 18.The compound of claim 14 wherein X is hydrogen and Y is 3-methoxy,namely 2-amino-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine.
 19. Thecompound of claim 14 wherein X is hydrogen and Y is 4-methyl, namely2-amino-4-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine.
 20. Thecompound of claim 14 wherein X is hydrogen and Y is 4-fluoro, namely2-amino-4-4-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine.
 21. Thecompound of claim 1 wherein A is ##STR17## R¹ is hydrogen and the moietyrepresented by the formula. ##STR18## is at the 5 position on the1,4,5,6-tetrahydropyrimidine ring.
 22. The compound of claim 21 whereinY is hydrogen.
 23. The compound of claim 22 wherein X is hydrogen. 24.The compound of claim 23 wherein R is methyl, namely2-methoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine.
 25. Thehydrochloride salt of the compound of claim
 24. 26. The compound ofclaim 23 wherein R is ethyl, namely2-ethoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine.
 27. Thecompound of claim 23 wherein R is isopropyl, namely2-isopropoxycarbonylamino-5-phenyl-1,4,5,6-tetrahydropyrimidine.
 28. Thecompound of claim 22 wherein X is chloro.
 29. The compound of claim 28wherein X is 2-chloro and R is methyl, namely2-methoxycarbonylamino-5-(2-chlorophenyl)-1,4,5,6-tetrahydropyrimidine.30. The compound of claim 22 wherein X is bromo.
 31. The compound ofclaim 30 wherein X is 3-bromo and R is methyl, namely2-methoxycarbonylamino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine.32. The compound of claim 30 wherein X is 3-bromo and R is n-propyl,namely2-n-propoxycarbonylamino-5-(3-bromophenyl)-1,4,5,6-tetrahydropyrimidine.33. The compound of claim 22 wherein X is methoxy.
 34. The compound ofclaim 33 wherein X is 3-methoxy and R is methyl, namely2-methoxycarbonylamino-5-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine.35. The compound of claim 22 wherein X is fluoro.
 36. The compound ofclaim 35 wherein X is 4-fluoro and R is methyl, namely2-methoxycarbonylamino-5-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine.37. The compound of claim 22 wherein X is alkyl of one through threecarbon atoms.
 38. The compound of claim 37 wherein X is 4-isopropyl andR is methyl, namely2-methoxycarbonylamino-5-(4-isopropylphenyl)-1,4,5,6-tetrahydropyrimidine.39. The compound of claim 21 wherein X and Y are both chloro.
 40. Thecompound of claim 39 wherein R is methyl.
 41. The compound of claim 40wherein X and Y are at the 3,4-positions, namely2-methoxycarbonylamino-5-(3,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.42. The compound of claim 40 wherein X and Y are at the 2,4-positions,namely2-methoxycarbonylamino-5-(2,4-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.43. The compound of claim 40 wherein X and Y are at the 2,6-positions,namely2-methoxycarbonylamino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.44. The compound of claim 39 wherein R is isopropyl.
 45. The compound ofclaim 44 wherein X and Y are at the 2,6-positions, namely2-isopropoxycarbonylamino-5-(2,6-dichlorophenyl)-1,4,5,6-tetrahydropyrimidine.46. The compound of claim 1 wherein A is ##STR19## R¹ is hydrogen andthe moiety represented by the formula ##STR20## is at the 4-position ofthe 1,4,5,6-tetrahydropyrimidine ring.
 47. The compound of claim 21wherein Y is hydrogen.
 48. The compound of claim 47 wherein X ishydrogen.
 49. The compound of claim 48 where R is methyl, namely2-methoxycarbonylamino-4-phenyl-1,4,5,6-tetratetrahydropyrimidine. 50.The compound of claim 48 wherein R is n-propyl, namely2-n-propoxy-carbonylamino-4-phenyl-1,4,5,6-tetrahydropyrimidine.
 51. Thecompound of claim 48 wherein X is trifluoromethyl.
 52. The compound ofclaim 51 wherein X is 2-trifluoromethyl and R is methyl, namely2-methoxycarbonylamino-4-(2-trifluoromethylphenyl)-1,4,5,6-tetrahydropyrimidine.53. The compound of claim 47 wherein X is methoxy.
 54. The compound ofclaim 53 wherein X is 3-methoxy and R is methyl, namely3-methoxycarbonylamino-4-(3-methoxyphenyl)-1,4,5,6-tetrahydropyrimidine.55. The compound of claim 47 wherein X is methyl.
 56. The compound ofclaim 55 wherein X is 4-methyl and R is methyl, namely4-methoxycarbonylamino-4-(4-methylphenyl)-1,4,5,6-tetrahydropyrimidine.57. The compound of claim 47 wherein X is fluoro.
 58. The compound ofclaim 57 wherein X is 4-fluoro and R is methyl, namely2-methoxycarbonylamino-4-(4-fluorophenyl)-1,4,5,6-tetrahydropyrimidine.59. A pharmaceutical composition which is useful for treating,palliating or preventing undesirable conditions in mammals involving thecentral nervous system and which comprises a therapeutically effectiveamount of a compound of claim 1 and at least one pharmaceuticallyacceptable excipient.